The most widely used addictive drug in the world is tobacco, of which the principal addictive component is nicotine. Approximately 19% of adults in the U.S. smoke cigarettes, and cigarette smoking accounts for one of every five deaths in the USA (Center for Disease Control and Prevention, Morbidity and Mortality Weekly Report, Centers for Disease Control, 61(44): 889-894 (2012)). In the lung, cigarette smoke causes chronic obstructive pulmonary disease (COPD) and lung cancer, and smoking is associated with an increased risk of cardiovascular disease and a variety of other neoplasms (see, e.g., Alberg et al., J. Clin. Oncol., 23: 3175-3185 (2005); Blanco-Cedres et al., Am. J. Epidemiol., 155: 354-360 (2002); Hylkema et al., Eur. Respir. J., 29: 438-445 (2007); and Sebelius K, How Tobacco Smoke Causes Disease: the Biology and Behavioral Basis for Smoking-Attributable Disease: a Report of the Surgeon General, U.S. Dept. of Health and Human Services (2010)). Smoking-related health care and loss of productivity cost in excess of $193 billion annually in the U.S. (Sebelius, supra).
Although each puff of cigarette smoke contains more than 4000 chemicals, the addictive properties of cigarette smoking are due to nicotine, a 162 Da alkaloid that represents 0.6-3.0% of dry weight of tobacco (see, e.g., National Cancer Institute (NCI) Tobacco Control Monograph, 9: 61 (2011); Church et al., Environ. Health Perspect., 64: 111-126 (1985); and Pryor et al., Ann. N. Y. Acad. Sci., 686: 12-27 (1993)). Most nicotine is pyrolized at the cigarette tip, but each cigarette typically delivers 1.0 to 1.5 mg nicotine that passes across the alveoli into the blood stream, taking about 10 to 19 seconds to reach the brain (see, e.g., Rose et al., Drug Alcohol Depend., 56: 99-107 (1999); Le Houezec, J., Int. J. Tuberc. Lung Dis., 7: 811-819 (2003); and Benowitz et al., Clin. Pharmacol. Ther., 35: 499-504 (1984)). In the brain, nicotine binds to the nicotinic acetylcholine receptor, triggering L-tyrosine to be converted to dopamine, with resulting pleasure, reduced stress, alterations in blood pressure and heart rate, heightened alertness and increased ability to process information (see, e.g., Tammimaki et al., Biochem. Pharmacol., 82(8): 808-19 (2011); Maskos, et al., Nature, 436: 103-107 (2005); and Benowitz, N. L., Annu. Rev. Pharmacol. Toxicol., 49: 57-71 (2009)).
Despite the devastating effects of nicotine addiction, the combined current strategies with drugs and counseling to help smokers quit are mostly ineffective, with a 70 to 80% recidivism rate within 6 months (see, e.g., Fiore, M. C., et al., Treating Tobacco Use and Dependence: 2008 Update, U.S. Dept. of Health and Human Services). One approach to treating nicotine addiction has been to develop an anti-nicotine vaccine. Anti-nicotine vaccines attempt to generate a host immune response to evoke humoral immunity against nicotine. The challenge of this approach is that nicotine is a small molecule not seen by the immune system, and thus nicotine (or a nicotine analog) must be coupled to a larger molecule to induce an anti-nicotine immune response (Lesage et al., AAPS. J., 8: E65-E75 (2006); Moreno et al., Pharmacol. Biochem. Behay., 92: 199-205 (2009); and Maurer et al., Eur. J. Immunol., 35: 2031-2040 (2005)). For example, AM1, a trans-3′-(hydroxymethyl) nicotine-derived nicotine hapten with a linker containing an ether moiety and a free carboxyl group for conjugation (Moreno et al., Mol. Pharm., 7: 431-441 (2010)) has been attached to carriers such as tetanus toxin to create an anti-nicotine vaccine. In a rodent self-administration model, this vaccine shifted preference for nicotine self-administration (see Moreno et al., Mol. Pharm., 7: 431-441 (2010)). Three active immunotherapy vaccines have been tested in clinical trials, including TA-NIC (a nicotine analog linked to cholera toxin B, Xenova), NicVAX (a nicotine analog linked to Pseudomonas aeruginosa exoprotein A, Nabi Pharmaceuticals), and NicQb (a nicotine analog linked to particles of the bacteriophage Qβ, Cytos Biotechnology) (see Polosa et al., Trends Pharmacol. Sci., 32: 281-289 (2011); and Hatsukami et al., Clin. Pharmacol. Ther., 89: 392-399 (2011)). These vaccines are well tolerated, and the individuals with the highest levels of antibodies were more likely to abstain from smoking (see Polosa et al., supra). However, all trials showed large variation among trial participants in the amount of antibody generated, and only a relatively small percentage of the participants have abstained from smoking (see Polosa et al., supra, Hatsukami et al., supra; Maurer et al., Expert. Opin. Investig. Drugs, 16: 1775-1783 (2007); and Pollack, A., “Antismoking Vaccine Fails in Late Trial,” The New York Times (Jul. 18, 2011)).
Thus, there is a need for alternative compositions and methods to prevent or treat nicotine addiction. This invention provides such compositions and methods. This and other advantages of the invention will become apparent from the detailed description provided herein.